A significant neurodevelopmental disorder associated with a South Asian founder mutation in the UFMylation adaptor CDK5RAP3 - Report - MDSpire

A significant neurodevelopmental disorder associated with a South Asian founder mutation in the UFMylation adaptor CDK5RAP3

  • By

  • Michaela Yuen

  • Katharine Zhang

  • Rhett G. Marchant

  • Ryosuke Ishimura

  • Mark Graham

  • May Aung-Htut

  • Samantha Bryen

  • Rocio Rius

  • Lee Marshall

  • Nader Aryamanesh

  • Gregory Dziaduch

  • Himanshu Joshi

  • Ben Weisburd

  • Steve D. Wilton

  • Meredith Wilson

  • Russell Gear

  • Lucy Hennington

  • Stephanie Lau

  • Helen Doyle

  • Michael Krivanek

  • Richard J. Leventer

  • Susan M. White

  • Sarah A. Sandaradura

  • Masaaki Komatsu

  • Frances J. Evesson

  • Sandra T. Cooper

  • April 27, 2026

  • 0 min

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Clinical Report: Neurodevelopmental Disorder Linked to CDK5RAP3 Mutation

Overview

This report highlights the association of biallelic CDK5RAP3 variants with a lethal neurodevelopmental disorder in three individuals from two unrelated families. The findings underscore the critical role of CDK5RAP3 in neurodevelopment and its potential implications for genetic testing in affected populations.

Background

UFMylation is a post-translational modification that plays a significant role in various cellular processes, including the stress response and protein quality control. Recent studies have linked mutations in UFMylation pathway genes to severe neurodevelopmental disorders. The identification of CDK5RAP3 as a contributor to these disorders emphasizes the need for awareness and genetic evaluation in affected populations, particularly in South Asian communities where a founder mutation may be prevalent.

Data Highlights

No numerical data or trial data available in the source material.

Key Findings

  • Biallelic variants in CDK5RAP3 are associated with a lethal neurodevelopmental disorder.
  • Clinical features include global developmental delay, epileptic encephalopathy, and ataxia.
  • CDK5RAP3 plays a vital role in UFMylation, affecting cellular functions such as cell adhesion and cycle regulation.
  • Pathogenic variants in UFMylation pathway genes have been linked to various neurodevelopmental disorders.
  • Genetic testing for CDK5RAP3 mutations should be considered in South Asian populations with neurodevelopmental disorders.

Clinical Implications

Healthcare professionals should consider the role of CDK5RAP3 in neurodevelopmental disorders when evaluating patients, particularly in South Asian populations. Early genetic testing may facilitate timely diagnosis and management of affected individuals.

Conclusion

The discovery of CDK5RAP3 variants linked to severe neurodevelopmental disorders highlights the importance of genetic evaluation in clinical practice and the need for further research into UFMylation's role in human health.

References

  1. Acta Neuropathologica, 2026 -- Exploring the Genetic Underpinnings of Focal Cortical Dysplasia: Insights from a Large Cohort Analysis
  2. Nature Reviews Molecular Cell Biology, 2026 -- The mechanistic basis and cellular functions of UFMylation
  3. HealthyChildren.org -- Genetic Evaluation for Neurodevelopmental Disorders: New Guidance
  4. Brain — Disruption of Chloride Homeostasis and GABA-Induced Depolarization in MTOR-Associated Cortical Development Anomalies
  5. Brain — Modelling fragile X-associated neuropsychiatric disorders in young inducible 90CGG premutation mice
  6. Brain — Characterization of Clinical Features and Genetic Aspects of a Neurodevelopmental Disorder Linked to RBL2 Mutations
  7. National Rapid Genome Sequencing in Neonatal Intensive Care
  8. The mechanistic basis and cellular functions of UFMylation | Nature Reviews Molecular Cell Biology
  9. Genetic Evaluation for Neurodevelopmental Disorders: New Guidance - HealthyChildren.org

Original Source(s)

A significant neurodevelopmental disorder associated with a South Asian founder mutation in the UFMylation adaptor CDK5RAP3

  • by Michaela Yuen, Katharine Zhang, Rhett G. Marchant, Ryosuke Ishimura, Mark Graham, May Aung-Htut, Samantha Bryen, Rocio Rius, Lee Marshall, Nader Aryamanesh, Gregory Dziaduch, Himanshu Joshi, Ben Weisburd, Steve D. Wilton, Meredith Wilson, Russell Gear, Lucy Hennington, Stephanie Lau, Helen Doyle, Michael Krivanek, Richard J. Leventer, Susan M. White, Sarah A. Sandaradura, Masaaki Komatsu, Frances J. Evesson, Sandra T. Cooper

  • April 27, 2026

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